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WO2008064015A1 - Procédés pour préserver la fonction rénale au moyen d'inhibiteurs de xanthine oxydoréductase - Google Patents

Procédés pour préserver la fonction rénale au moyen d'inhibiteurs de xanthine oxydoréductase Download PDF

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Publication number
WO2008064015A1
WO2008064015A1 PCT/US2007/084573 US2007084573W WO2008064015A1 WO 2008064015 A1 WO2008064015 A1 WO 2008064015A1 US 2007084573 W US2007084573 W US 2007084573W WO 2008064015 A1 WO2008064015 A1 WO 2008064015A1
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WIPO (PCT)
Prior art keywords
substituted
subject
group
unsubstituted
phenyl
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PCT/US2007/084573
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English (en)
Inventor
Christopher Lademacher
Patricia Macdonald
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Takeda Pharmaceuticals North America
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Application filed by Takeda Pharmaceuticals North America filed Critical Takeda Pharmaceuticals North America
Priority to AU2007323919A priority Critical patent/AU2007323919A1/en
Priority to KR20157001953A priority patent/KR20150024919A/ko
Priority to CN200780049607A priority patent/CN101677999A/zh
Priority to CA002669935A priority patent/CA2669935A1/fr
Priority to RU2009122505/15A priority patent/RU2508099C2/ru
Priority to KR1020167005469A priority patent/KR20160031040A/ko
Priority to EP07864338A priority patent/EP2101761A4/fr
Priority to JP2009536541A priority patent/JP2010509372A/ja
Priority to MX2009004984A priority patent/MX2009004984A/es
Priority to KR1020097012310A priority patent/KR20090103879A/ko
Priority to BRPI0718611-8A2A priority patent/BRPI0718611A2/pt
Publication of WO2008064015A1 publication Critical patent/WO2008064015A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to methods of treating subjects in order to preserve renal function. More specifically, the present invention involves administering to a subject in need of preservation of renal function a therapeutically effective amount of at least one xanthine oxidoreductase inhibiting compound or salt thereof in order to preserve the renal function of such patients.
  • subjects are viewed as having normal renal function when their serum creatinine levels are ⁇ 1.5 mg/dL and their creatinine clearance is > 50 mL/min. If the serum creatinine level becomes greater than 1.5 mg/dL, or if the creatinine clearance falls below 50 mL/min., the subject is deemed to be renally impaired.
  • Another important measure of renal function is glomerular filtration rate or GFR. GFR is calculated by comparing urine creatinine levels with blood test results and is believed to give a more precise indication of the state of the kidneys. For most patients, a GFR over 60 ml/minute is adequate. If the GFR has significantly declined from a previous test result, however, this can be an early indicator of kidney disease requiring medical intervention.
  • renal function can be assessed by measuring urinary protein excretion and glomerular hemodynamics (include whole kidney GFR, single-nephron GFR, glomerular pressure and flow, afferent resistance and efferent resistance) using renal micropuncture technique, among other methods known to those skilled in the art.
  • urinary protein excretion and glomerular hemodynamics include whole kidney GFR, single-nephron GFR, glomerular pressure and flow, afferent resistance and efferent resistance
  • renal micropuncture technique among other methods known to those skilled in the art.
  • renal histological evaluation for vacuolar degeneration of renal proximal tubules, tubulo interstitial fibrosis and thickening of the afferent arteriolar vascular wall can be used to further understand the causes or etiology of renal diseases.
  • Gout is characterized by the symptomatic deposition of urate crystals in joint tissues as a result of urate supersaturation of extracellular fluids, a biochemical aberration reflected by hyperuricemia (serum urate levels exceeding 7.0 mg/dL in men and exceeding 6.0 mg/dL in women).
  • hyperuricemia serum urate levels exceeding 7.0 mg/dL in men and exceeding 6.0 mg/dL in women.
  • renal calculi or "stones” occur with a frequency of 10-25% and in those patients approximately 1% will manifest the development of a uric acid renal calculus on an annual basis.
  • Uric acid lowering therapy is recommended for subjects suffering from gout and one or more of the following conditions: acute gouty arthritis, chronic gouty joint disease, tophaceous gout, uric acid nephropathy, and/or nephrolithiasis (kidney stones).
  • acute gouty arthritis chronic gouty joint disease
  • tophaceous gout tophaceous gout
  • uric acid nephropathy and/or nephrolithiasis (kidney stones).
  • kidney stones nephrolithiasis
  • the present invention relates to a method of preserving renal function in a subject in need thereof, the method including the step of administering to the subject a therapeutically effective amount of a xanthine oxidoreductase inhibitor or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method of preserving renal function in a subject in need thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound comprises the formula:
  • Ri and R 2 are each independently a hydrogen, a hydro xyl group, a COOH group, an unsubstituted or substituted C 1 -C 10 alkyl group, an unsubstituted or substituted C 1 -C 10 alkoxy, an unsubstituted or substituted hydro xyalkoxy, a phenylsulfmyl group or a cyano (-CN) group;
  • R 3 and R 4 are each independently a hydrogen or A, B, C or D as shown below:
  • T connects A, B, C or D to the aromatic ring shown above at R 1 , R 2 , R3 or R 4 .
  • R 5 and R 6 are each independently a hydrogen, a hydro xyl group, a COOH group, an unsubstituted or substituted C 1 -C 10 alkyl group, an unsubstituted or substituted C 1 -C 10 alkoxy, an unsubstituted or substituted hydro xyalkoxy, COO-Glucoronide or COO-Sulfate;
  • R 7 and Rs are each independently a hydrogen, a hydro xyl group, a COOH group, an unsubstituted or substituted C 1 -C 10 alkyl group, an unsubstituted or substituted C 1 -C 10 alkoxy, an unsubstituted or substituted hydro xyalkoxy, COO-Glucoronide or COO-Sulfate;
  • R9 is an unsubstituted pyridyl group or a substituted pyridyl group; and wherein Rio is a hydrogen or a lower alkyl group, a lower alkyl group substituted with a pivaloyloxy group and in each case, Rio bonds to one of the nitrogen atoms in the 1, 2, 4-triazole ring shown above.
  • the present invention relates to a method of preserving renal function in a subject in need of thereof, the method comprising the step of administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound comprises the formula:
  • Rn and R12 are each independently a hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl, or Rn and R12 may together form a four- to eight-membered carbon ring together with the carbon atom to which they are attached;
  • Ri 3 is a hydrogen or a substituted or unsubstituted lower alkyl group;
  • R 14 is one or two radicals selected from a group consisting of a hydrogen, a halogen, a nitro group, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted phenyl, --OR16 and -SO 2 NR 17 R 17 ', wherein Ri 6 is a hydrogen, a substituted or unsubstituted lower alkyl, a phenyl-substituted lower alkyl, a carboxymethyl or ester thereof, a hydro xyethyl or ether thereof
  • a subject being treated pursuant to the methods of the invention can have one or more of the following conditions: hyperuricemia, gout, acute gouty arthritis, chronic gouty joint disease, tophaceous gout, uric acid nephropathy, or nephrolithiasis.
  • the subject may be suffering from a progressive renal disease, including, but not limited to, renal tubulo interstitial diseases, renal tubular cell injury, nephritis, glomerular diseases, glomerulonephritides, renal ischemia, renal ischemia/reperfusion injury, renal vascular diseases, renal artery or vein thrombosis, interstitial nephritis, toxic glomerulophathies, renal stones/nephrolithiasis, long standing hypertension, diabetic nephropathy, congestive heart failure, nephropathy from sickle cell anemia and other blood dyscrasias, nephropathy related to hepatitis, HIV, parvovirus and BK virus (a human polyomavirus), cystic kidney diseases, lupus nephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis, focal glomerular sclerosis, vasculitis, cryoglob
  • Subjects being treated can also have impaired renal function as measured by known medical test methods. For example, subjects being treated can have a serum creatinine level of > 1.5 mg/dL or a creatinine clearance of ⁇ 50 mL/minute. Similarly, subjects being treated can have a GFR of ⁇ 60mg/minute. However, the subject being treated by the methods of the invention need not have any particular condition or impairment if it is determined that preservation or stabilization of renal function is medically necessary or desirable.
  • Figure 1 shows the effect of febuxostat (Fx) on body weight (BW) in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Fx febuxostat
  • BW body weight
  • RK remnant kidney
  • OA oxonic acid
  • Figure 2 shows the effect of febuxostat (Fx) on plasma uric acid (UA) in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Fx febuxostat
  • UA plasma uric acid
  • RK remnant kidney
  • OA oxonic acid
  • Figure 3 shows the effect of febuxostat (Fx) on systolic blood pressure (SBP) in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Fx febuxostat
  • SBP systolic blood pressure
  • RK remnant kidney
  • OA oxonic acid
  • Figure 4 shows the effect of febuxostat (Fx) on mean arterial pressure (under anesthesia) in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Figure 5 shows the effect of febuxostat (Fx) on proteinuria in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • -•- shows the proteinuria of RK rats only (control);
  • -o- shows the proteinuria of RK rats treated with Fx;
  • - ⁇ - shows the proteinuria of RK rats treated with OA; and
  • -D- shows the proteinuria of RK treated with OA and Fx.
  • Figure 6 shows the effect of febuxostat (Fx) on glomerular filtration rate in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Figure 7 shows the effect of febuxostat (Fx) on glomerular hemodynamics in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Figure 8 shows the effect of febuxostat (Fx) on renal arteriolar morphology in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Figure 9 shows the effect of febuxostat (Fx) on renal tubulo interstitial fibrosis in remnant kidney (RK) rats with and without coexisting oxonic acid (OA)-induced hyperuricemia.
  • Fx febuxostat
  • administer refers to any manner of providing a drug (such as, a xanthine oxidoreductase inhibitor or a salt thereof) to a subject or patient.
  • routes of administration can be accomplished through any means known by those skilled in the art. Such means include, but are not limited to, oral, buccal, intravenous, subcutaneous, intramuscular, by inhalation and the like.
  • progressive renal disease As used herein, the phrases “progressive renal disease”, “end stage renal disease”,
  • chronic renal failure CRF
  • chronic renal disease CRD
  • chronic kidney disease CKD
  • progressive renal disease, end stage renal disease, chronic kidney disease or chronic renal injury includes, but is not limited to, conditions or dysfunctions caused by renal tubulo interstitial diseases, renal tubular cell injury, chronic infections, chronic inflammation, nephritis, glomerular diseases, glomerulonephritides, renal ischemia, renal ischemia/reperfusion injury, vascular diseases, renal artery or vein thrombosis, interstitial nephritis, drugs, toxins, trauma, renal stones/nephrolithiasis, chronic hyperuricemia, long standing hypertension, diabetes, congestive heart failure, nephropathy from sickle cell anemia and other blood dyscrasias, nephropathy related to hepatitis, HIV, parvovirus and BK virus (a human polyomavirus), cystic kidney diseases, congenital malformations, obstruction, malignancy, kidney disease of indeterminate causes, lupus nephritis, membranous glomeruloneph
  • the term "pharmaceutically acceptable” includes moieties or compounds that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • the term "subject” refers to an animal, preferably a mammal, including a human or non-human.
  • patient and subject may be used interchangeably herein.
  • the terms "therapeutically effective amount” or “prophylactically effective amount” of a drug refers to a nontoxic but sufficient amount of the drug to provide the desired effect of preserving renal function in a subject.
  • these terms mean a sufficient amount of, for example, the composition, xanthine oxidoreductase inhibiting compound, or formulation necessary to preserve the subject's renal function, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of a pharmaceutical composition of the invention will be decided by a patient's attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective or prophylactically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and other factors known to those of ordinary skill in the medical arts.
  • the amount of drug that is "effective” or “prophylactic” will vary from subject to subject, depending on the age and general condition of the individual, the particular drug or drugs, and the like. Thus, it is not always possible to specify an exact “therapeutically effective amount” or a “prophylactically effective amount”. However, an appropriate
  • terapéuticaally effective amount or “prophylactically effective amount” in any individual case may be determined by one skilled in the art.
  • treating and “treatment” refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
  • “treating” a patient involves prevention of a particular disorder or adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual by inhibiting or causing regression of a disorder or disease.
  • xanthine oxidoreductase inhibitor refers to any compound that (1) is an inhibitor of a xanthine oxidoreductase, such as, but not limited to, xanthine oxidase; and (2) chemically, does not contain a purine ring in its structure (i.e. is a "non-purine”).
  • xanthine oxidoreductase inhibitor as defined herein also includes metabolites, polymorphs, solvates and prodrugs of the such compounds, including metabolites, polymorphs, solvates and prodrugs of the exemplary compounds described as Formula I and Formula II below.
  • xanthine oxidoreductase inhibitors include, but are not limited to, 2-[4-(2- carboxypropoxy)-3-cyanophenyl]-4-methyl-5-thiazolecarboxylic acid and compounds having the following Formula I or Formula II:
  • Ri and R 2 are each independently a hydrogen, a hydro xyl group, a COOH group, an unsubstituted or substituted Ci-Cio alkyl group, an unsubstituted or substituted Ci-Cio alkoxy, an unsubstituted or substituted hydroxyalkoxy, a phenylsulfmyl group or a cyano (-CN) group; wherein R 3 and R 4 are each independently a hydrogen or A, B, C or D as shown below:
  • T connects or attaches A, B, C or D to the aromatic ring shown above at Ri, R 2 , R 3 or R 4 .
  • R 5 and R 6 are each independently a hydrogen, a hydro xyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
  • R 7 and Rs are each independently a hydrogen, a hydro xyl group, a COOH group, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C1-C10 alkoxy, an unsubstituted or substituted hydroxyalkoxy, COO-Glucoronide or COO-Sulfate;
  • R9 is an unsubstituted pyridyl group
  • Rn and R12 are each independently a hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl (the substituted phenyl in this Formula II refers to a phenyl substituted with a halogen or lower alkyl, and the like.
  • Rn and R 12 may together form a four- to eight- membered carbon ring together with the carbon atom to which they are attached;
  • Ri 3 is a hydrogen or a substituted or unsubstituted lower alkyl group;
  • R 14 is one or two radicals selected from a group consisting of a hydrogen, a halogen, a nitro group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted phenyl (the substituted phenyl in this Formula II refers to a phenyl substituted with a halogen or lower alkyl group, and the like.
  • Examples include, but are not limited to, p-tolyl and p-chlorophenyl), -ORi 6 and -SO2NR17R1V, wherein Ri 6 is a hydrogen, a substituted or unsubstituted lower alkyl, a phenyl-substituted lower alkyl, a carboxymethyl or ester thereof, a hydro xyethyl or ether thereof, or an allyl; Rn and R 17 - are each independently a hydrogen or a substituted or unsubstituted lower alkyl group; wherein Ri 5 is a hydrogen or a pharmaceutically active ester- forming group; wherein A is a straight or branched hydrocarbon radical having one to five carbon atoms; wherein B is a halogen, an oxygen, or a ethylenedithio; wherein Y is an oxygen, a sulfur, a nitrogen or a substituted nitrogen; wherein Z is an oxygen, a nitrogen or a substituted nitrogen; and the
  • lower alkyl(s) group refers to a C 1 -C 7 alkyl group, including, but not limited to, including methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, hexyl, heptal and the like.
  • lower alkoxy refers to those groups formed by the bonding of a lower alkyl group to an oxygen atom, including, but not limited to, methoxy, ethoxy, pro poxy, isopropoxy, butoxy, isobutoxy, pentoxy, hexoxy, heptoxy and the like.
  • lower alkylthio group refers to those groups formed by the bonding of a lower alkyl to a sulfur atom.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • substituted pyridyl refers to a pyridyl group that can be substituted with a halogen, a cyano group, a lower alkyl, a lower alkoxy or a lower alkylthio group.
  • four- to eight-membered carbon ring refers to cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • ester-forming group refers to a group which binds to a carboxyl group through an ester bond.
  • ester- forming groups can be selected from carboxy-protecting groups commonly used for the preparation of pharmaceutically active substances, especially prodrugs.
  • said group should be selected from those capable of binding to compounds having Formula II wherein R 15 is hydrogen through an ester bond.
  • Resultant esters are effective to increase the stability, solubility, and absorption in gastrointestinal tract of the corresponding non-esterified forms of said compounds having Formula II, and also prolong the effective blood-level of it.
  • ester bond can be cleaved easily at the pH of body fluid or by enzymatic actions in vivo to provide a biologically active form of the compound having Formula II.
  • Preferred pharmaceutically active ester- forming groups include, but are not limited to, 1 -(oxygen substituted)-C2 to C 15 alkyl groups, for example, a straight, branched, ringed, or partially ringed alkanoyloxyalkyl groups, such as acetoxymethyl, acetoxyethyl, propionyloxymethyl, pivaloyloxymethyl, pivaloyloxyethyl, cyclohexaneacetoxyethyl, cyclohexanecarbonyloxycyclohexylmethyl, and the like, C 3 to C 15 alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl, isopropoxycarbonyloxypropyl
  • esters as used in the phrase “the ester of carboxymethyl” refers to a lower alkyl ester, such as methyl or ethyl ester; and the term “ether” used in the phrase “the ether of hydro xyethyl” means an ether which is formed by substitution of the hydrogen atom of hydro xyl group in the hydro xyethyl group by aliphatic or aromatic alkyl group, such as benzyl.
  • the carboxy-protecting groups may be substituted in various ways.
  • substituents include halogen atom, alkyl groups, alkoxy groups, alkylthio groups and carboxy groups.
  • straight or branched hydrocarbon radical in the definition of A in Formula II above refers to methylene, ethylene, propylene, methylmethylene, or isopropylene.
  • substituent of the "substituted nitrogen" in the definition of Y and Z in Formula II above are hydrogen, lower alkyl, or acyl.
  • phenyl-substituted lower alkyl refers to a lower alkyl group substituted with phenyl, such as benzyl, phenethyl or phenylpropyl.
  • prodrug refers to a derivative of the compounds shown in the above-described Formula I and Formula II that have chemically or metabolically cleavable groups and become by so lvo lysis or under physiological conditions compounds that are pharmaceutically active in vivo.
  • Esters of carboxylic acids are an example of prodrugs that can be used in the dosage forms of the present invention.
  • Methyl ester prodrugs may be prepared by reaction of a compound having the above-described formula in a medium such as methanol with an acid or base esterif ⁇ cation catalyst (e. g., NaOH, H 2 SO 4 ).
  • Ethyl ester prodrugs are prepared in similar fashion using ethanol in place of methanol.
  • Examples of compounds having the above Formula I are: 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (also known as "febuxostat"), 2-[3- cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, 2-[3-cyano- 4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, 2-(3-cyano-4- hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid, 2-[4-(2-carboxypropoxy)-3-cyanophenyl]- 4-methyl-5-thiazolecarboxylic acid, l-(3-cyano-4-(2,2-dimethylpropoxy)phenyl)-lH-pyrazole-4- carboxylic acid, l-3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-lH-pyr
  • Preferred compounds having the above Formula I are: 2-[3-cyano-4-(2- methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid, 2-[3-cyano-4-(3-hydroxy-2- methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, 2-[3-cyano-4-(2-hydroxy-2- methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid, 2-(3-cyano-4-hydroxyphenyl)-4- methyl-5 -thiazo lecarboxylic acid, 2- [4-(2-carboxypropoxy)-3 -cyanophenyl] -4-methyl-5 - thiazolecarboxylic acid.
  • xanthine oxidoreductase inhibiting compounds can be found using xanthine oxidoreductase and xanthine in assays to determine if such candidate compounds inhibit conversion of xanthine into uric acid. Such assays are well known in the art.
  • the present invention relates to methods of preserving renal function in subjects in need thereof. It has been discovered that a class of compounds known as xanthine oxidoreductase inhibitors can be used not only to reduce serum urate levels in subjects, but also to preserve renal function in said subjects over time.
  • the xanthine oxidoreductase inhibitors of the present invention are effective in reducing serum urate levels, these compounds can be used to treat subjects suffering from hyperuricemia, gout, acute gouty arthritis, chronic gouty disease, tophaceous gout, uric acid nephropathy, and/or nephrolithiasis.
  • Such treatments involve the administration of sufficient amounts of xanthine oxidoreductase inhibitor to reduce uric acid levels in the subject with a quick onset (namely, within one week of first beginning treatment with a xanthine oxidoreductase inhibitor (See, Becker M, Kisicki J, Khosravan R, Wu J, Mulford D, Hunt B, MacDonald P, Joseph-Ridge N., Nucleosides Nucleotides Nucleic Acids, 23(8 & 9):1111-1116 (October 2004)) and maintain a reduction in the subject's serum urate level for a prolonged period, preferably for at least 4 weeks (See, Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Palo WA, Eustace D, Vernillet L, Joseph-Ridge N, Arthritis Rheum., 52(3):916-923 (March 2005)), more preferably for at least a year, still more preferably for at least
  • xanthine oxidoreductase inhibitors in quantities that are effective to reduce a subject's serum urate level for such prolonged periods is also therapeutically effective in preserving the subject's renal function during such periods.
  • Preservation of renal function can be assessed by well-known measures, such as creatinine levels, creatinine clearance, and the GFR. It will be understood that preservation of renal function entails not only better renal function in xanthine oxidoreductase inhibitor-treated subjects than in placebo-treated subjects, but also maintaining renal function reasonably close to baseline levels, i.e., at stable levels, not necessarily improving renal function from reduced or impaired levels to adequate levels.
  • xanthine oxidoreductase inhibitors While administration of xanthine oxidoreductase inhibitors is effective to preserve renal function at the subject's existing levels, i.e., stabilize renal function, it is not necessarily effective to improve renal function significantly beyond those levels. Nevertheless, maintaining existing levels of renal function is of importance to subjects suffering from conditions like hyperuricemia, gout, acute gouty arthritis, chronic gouty disease, tophaceous gout, uric acid nephropathy, and/or nephrolithiasis, since it may slow the progression of kidney disease in such patients.
  • preserving the subject's renal function involves maintaining the subject's GFR at a level of at least approximately 75% or greater when compared to the subject's baseline levels; more preferably, at a level of at least approximately 80% or greater when compared to the subject's baseline levels; and, still more preferably, at a level of at least approximately 90% or greater when compared to the subject's baseline levels.
  • the administration of the xanthine oxidoreductase inhibitors of the present invention can also be used to preserve the renal function in subjects suffering from progressive renal disease.
  • Such subjects may or may not also be suffering from hyperuricemia, gout, acute gouty arthritis, chronic gouty disease, tophaceous gout, uric acid nephropathy, and/or nephrolithiasis.
  • the treatment of subjects suffering from progressive renal disease involves the administration of sufficient amounts of xanthine oxidoreductase inhibitor to maintain or improve renal function in a subject with a quick onset (namely, within two weeks of first beginning treatment with a xanthine oxidoreductase inhibitor) and maintain such improved renal function in the subject for a prolonged period, preferably for at least 4 weeks, more preferably for at least a year, still more preferably for at least two years, and still more preferably for in excess of 30 months and beyond.
  • the methods described previously herein for measuring the preservation of renal function can also be used to measure the preservation of renal function in subjects suffering from progressive renal disease.
  • preservation of renal function entails not only better renal function in xanthine oxidoreductase inhibitor-treated subjects than in placebo-treated subjects, but also maintaining renal function reasonably close to baseline levels, i.e., at stable levels, not necessarily improving renal function from reduced or impaired levels to adequate levels.
  • administration of xanthine oxidoreductase inhibitors is effective to preserve renal function at the subject's existing levels, i.e., stabilize renal function, it is not necessarily effective to improve renal function significantly beyond those levels.
  • maintaining existing levels of renal function is of importance to subjects suffering from progressive renal disease, since it may slow the progression of the disease in such patients.
  • compositions containing at least one xanthine oxidoreductase inhibitor are contemplated for use in the methods of the present invention.
  • formulations containing such combinations are a matter of choice for those skilled in the art.
  • coatings or other separation techniques may be used in cases where the combination of compounds are incompatible.
  • compositions for use in accordance with the methods of the present invention can be provided in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
  • Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1 et seq. (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds or separately by reacting a free base function with a suitable organic acid.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and unde
  • basic nitrogen- containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such as decyl
  • acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydro bromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
  • Basic addition salts can be prepared in situ during the final isolation and purification of compounds by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
  • the at least one xanthine oxidoreductase inhibiting compound or salts thereof may be formulated in a variety of ways that is largely a matter of choice depending upon the delivery route desired.
  • solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the xanthine oxidoreductase inhibiting compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as, but not limited to, starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as, but not limited to, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants, such as, but not limited to glycerol; d) disintegrating agents, such as, but not limited to, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents, such as, but not limited to, paraffin; f) absorption accelerators, such as, but not limited to, quatern
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as, but not limited to, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydro fur fury 1 alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and e
  • compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegradable polymer.
  • compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include, but are not limited to, water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
  • compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Suspensions in addition to the active compounds (i.e., xanthine oxidoreductase inhibiting compounds or salts thereof), may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, micro crystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, micro crystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • the drug i.e. xanthine oxidoreductase inhibiting compounds or salts thereof
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming micro eneapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Dosage forms for topical administration of the compounds of this present invention include powders, sprays, ointments and inhalants.
  • the active compound(s) is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • formulations used in accordance with the present invention generally will comprise a therapeutically effective amount of one or more xanthine oxidoreductase inhibiting compounds.
  • Formulations of the present invention are administered and dosed in accordance with sound medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medical practitioners.
  • the daily therapeutically effective or prophylactically effective amount of the xanthine oxidoreductase inhibiting compounds administered to a patient in single or divided doses range from about 0.01 to about 750 milligram per kilogram of body weight per day (mg/kg/day). More specifically, a patient may be administered from about 5.0 mg to about 300 mg once daily, preferably from about 20 mg to about 240 mg once daily and most preferably from about 40 mg to about 120 mg once daily of xanthine oxidoreductase inhibiting compounds.
  • Example 1 Information was collected prospectively in a subgroup of 18 human subjects with a history of nephrolithiasis, as reported by the subjects prior to study enrollment.
  • subjects were randomly assigned to one or four treatment arms: (1) febuxostat 40 mg per day, (2) febuxostat 80 mg per day, (3) febuxostat 120 mg per day, or (4) placebo.
  • Subjects completing the double-blind study entered an open-label, long-term study and began treatment with 80 mg febuxostat per day.
  • Febuxostat doses could be titrated over the initial 6 months to 40 mg or 120 mg febuxostat per day based on the subjects' serum urate levels and the occurrence of adverse events.
  • Table 2 provides a summary of renal function measures and longer-term serum urate response in subjects completing > 30 months of treatment.
  • Subject #2 had a calcium oxylate stone on Day 1005 of study with a sUA 4.2 mg/dL while receiving febuxostat 80 mg/day. This subject had a second calcium oxylate stone on Day 1265.
  • e Subject #13 had a calcium oxylate stone on Day 17 of DB study with a sUA of 13.4 mg/dL while receiving placebo and an additional calcium oxylate stone on Day 38 of the OL study while receiving febuxostat.
  • Table 3 provides a summary of the primary reason subjects prematurely discontinued participation.
  • Table 4 provides a summary of the most frequent adverse events occurring during the study.
  • NEC not elsewhere classified a Adverse events as reported by >3 subjects in the open-label study.
  • Example 1 illustrates that renal function was maintained at generally stable levels in the subjects receiving febuxostat throughout the study.
  • mice of the species/strain B6C3F1 of an initial age of 6 weeks were dosed via oral gavage with febuxostat suspended in 0.5% methyl cellulose.
  • the daily dose administered was either 0 mg (i.e., the control group), 3 mg, 12 mg, 24 mg, or 48 mg. Histopathological examination of the kidney was carried out after 13-weeks of dosing for vacuolar degeneration of renal proximal tubules (a known naturally occurring change in rodents). The results are shown in Table 5.
  • Example 2 illustrates that administration of febuxostat reduced the amount of vacuolar degeneration of the renal proximal tubules in a statistically significant fashion in the male animals studied.
  • Oxonic acid (OA) (Sigma-Aldrich, St Louis MO, USA), administered at 750 mg/kg body weight daily by oral gavage, was given starting the day after the 5/6 nephrectomy. Beginning immediately following the surgery, febuxostat was administered in drinking water at 30 mg/L (3-4 mg/kg/day), whereas the respective controls received only drinking water (with 3.5 mg/L of NaCl added to keep an equivalent salt concentration to the Fx-containing water). All groups were treated for four weeks. Body weight (beginning just before surgery) and food and water intakes were measured daily.
  • Systolic blood pressure measured in conscious rats by a tail cuff sphygmomanometer, and plasma uric acid (UA) levels were measured at just before surgery (namely, at baseline) and at the end of the four weeks. Proteinuria was measured at baseline and at the end of two and four weeks. A renal micropuncture procedure along with systemic blood pressure monitoring under pentobarbital anesthesia was performed at the end of four weeks followed by morphologic evaluation of the renal preglomerular microvasculature.
  • Rats were maintained under euvolemic conditions by infusion of 10 mL/kg of body weight of isotonic rat plasma during surgery, followed by an infusion of 25% polyfructosan, at 2.2 ml/h (Inutest; Fresenius Kabi, Linz, Austria). After 60 minutes, five to seven samples of proximal tubular fluid were obtained to determine flow rate and polyfructosan concentrations.
  • Intratubular pressure under free-flow (FF) and stop-flow (SFP) conditions and peritubular capillary pressure (Pc) were measured in other proximal tubules with a servo-null device (Servo Nulling Pressure System; Instrumentation for Physiology and Medicine, San Diego, CA, USA).
  • Glomerular colloid osmotic pressure was estimated from protein concentrations obtained from blood of the femoral artery (Ca) and surface efferent arterioles (Ce). Polyfructosan was measured in plasma and urine samples by the anthrone-based technique described by Davidson and Sackner in "Simplification of the anthrone method for the determination of inulin in clearance studies," J Lab Clin Med.
  • the volume of fluid collected from individual proximal tubules was estimated from the length of the fluid column in a constant-bore capillary tube of known internal diameter.
  • concentration of tubular polyfructosan was measured by the micro fluorometric method described by Vurek and Pegram in "Fluorometric method for the determination of nanogram quantities of inulin," Anal Biochem 16:409-419 (1966), the contents of which are herein incorporated by reference. Specifically, using a 8-nL pipette, tubular fluid samples were transferred into capillary cuvettes sealed at one end and containing 3 ⁇ L of dimedone reagent (100 mg dimedone in 10 mL of 85% ortho-phosphoric acid). Each cuvette was sealed immediately after adding the samples.
  • Protein concentration in afferent and efferent samples was determined according to the method described by Viets et al. in "Determination of serum protein concentration in nano liter blood samples using fluorescamine or o-phthalaldehyde", Anal Biochem 88:513-521 (1978), the contents of which are herein incorporated by reference. Specifically, 5 nL of serum was mixed with 5 ⁇ L of borate buffer solution containing Brij and mercaptoethanol in a 100- ⁇ L glass capillary tube. Additionally, 5 ⁇ L of o-phthalaldehyde (OPT) reagent was added. The contents were mixed by centrifuging the capillary tube several times in a hematocrit centrifuge.
  • OPT o-phthalaldehyde
  • MAP, GFR, glomerular capillary hydrostatic pressure (PGC), single -nephron plasma flow (QA), afferent (AR), efferent (ER) and total (TR) resistances and Kf were calculated with the following equations previously reported in Brenner BM, "Nephron adaptation to renal injury or ablation", Am J Physiol 249:F324-F337, (1985), the contents of which are herein incorporated by reference:
  • PGC SFP + ⁇ a, where ⁇ a is the colloid osmotic pressure of plasma obtained from femoral artery blood;
  • SBP stolic blood pressure
  • XBP-100 Kent Scientific Co, Torrington, CT, USA
  • Plasma uric acid was quantified using a commercial kit (Diagnostic Chemicals Ltd, Charlottetown, PEI, Canada). Proteinuria was determined by turbidimetry by the method of trichloroacetic acid as described in Henry RJ et al, "Turbidimetric determination. of proteins with sulfo salicylic and tricholoro acetic acids", Proc Soc Exp Biol Med 92:748-751 (1956), the contents ofwhich are herein incorporated by reference.
  • kidneys were washed by perfusion with phosphate- buffered saline and then fixed with 4% paraformaldehyde. Renal biopsies were embedded in paraffin. Sections of 4- ⁇ m thick fixed tissue were stained with periodic acid Schiff (PAS) reagent and Masson's trichrome staining. Arteriolar morphology was assessed by indirect peroxidase immuno staining for alpha-smooth muscle actin (DAKO Corp, Carpinteria, CA, USA). Renal sections incubated with normal rabbit serum were used as negative controls for immuno staining against alpha smooth-muscle actin.
  • PAS periodic acid Schiff
  • the outline of the vessel and its internal lumen were generated using computer analysis to calculate the total medial area (outline - inline), in 10 arterioles per biopsy.
  • the media/lumen ratio was calculated by the outline/inline relationship (See, Sanchez-Lozada LG et al, "Mild hyperuricemia induces glomerular hypertension in normal rats", Am J Physiol Renal Physiol 283:F1105-F1110 (2002); Sanchez- Lozada LG, et al., "Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats," Kidney Int 67:237-247 (2005), the contents of each are herein incorporated by reference). Quantifications were performed blinded.
  • the degree of tubulo interstitial fibrosis was quantified in 10 non-crossed fields of cortex (100X) per biopsy. Slides were analyzed by light microscopy (Olympus BX51; Olympus American, Melville, NY, USA) and captured by a digital video camera (CoolSnap Pro; Media Cybernetics, Silver Spring, MD, USA). Pictures were processed on a computer and analyzed using Image Pro-Plus (version 5.0; Media Cybernetics, Silver Spring, MD, USA). Taking advantage of the capabilities of color recognition with this software, positive blue-stained areas (fibrosis) were selected and quantified in pixel units; glomeruli and vessels were previously excluded from the field. For each biopsy, the mean amount of positive blue-stained area was calculated by averaging the values from ten examined fields. Statistical Analysis
  • Baseline body weight was similar among all four treatment groups. After surgery, body weight decreased in all treatment groups; this was likely due to reduced food consumption during the first week following the 5/6 nephrectomy. From Week 2 to Week 4, animals ate normally and started to gain body weight. At the end of the study, there were no significant differences in body weight or body weight gain between the four treatment groups. In the two groups treated with febuxostat, rats generally tended to eat slightly less and water intake was generally significantly reduced compared to the RK control or RK + OA groups.
  • Plasma uric acid ( Figure 2).
  • GFR glomerular filtration rate
  • M/L ratios media/lumen (M/L) ratios among the various groups (See, Figure 8); however, there was a tendency for the M/L ratio to be lower in febuxostat-treated rats compared to their respective untreated cohorts.
  • Table 6 provides a summary of the effect of febuxostat on body weight, food and water intake in remnant kidney rats with and without coexisting hyperuricemia
  • RK remnant kidney
  • Fx febuxostat
  • OA oxonic acid (used to induce hyperuricemia).
  • Mean ⁇ SEM was calculated from the average of daily food or water intake over one week for each animal.
  • RK remnant kidney
  • Fx febuxostat
  • OA oxonic acid (used to induce hyperuricemia).
  • MAP mean arterial pressure
  • PGC glomerular capillary pressure
  • GFR glomerular filtration rate
  • SNGFR single-nephron GFR
  • QA glomerular plasma flow
  • AR afferent resistance
  • ER efferent resistance
  • Kf ultrafiltration coefficient.
  • Table 8 describes historic control values from normal male wistar rats.
  • febuxostat treatment prevented proteinuria and renal injury in RK rats with and without coexisting hyperuricemia. Moreover, because febuxostat helped preserve preglomerular vessel morphology, normal glomerular pressure was maintained even in the presence of systemic hypertension. This study highlights the importance of preservation of the autoregulatory capacity of remnant nephrons in order to retard the progression of renal disease. Therefore, febuxostat treatment reduces the functional and structural alterations induced by the progressive and extensive loss of renal tissue in a rat model of chronic renal disease alone or in combination with coexisting hyperuricemia.

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Abstract

La présente invention concerne des procédés pour préserver la fonction rénale chez un individu qui en a besoin, par administration d'une quantité thérapeutiquement efficace d'au moins un composé d'inhibition de xanthine oxydoréductase ou d'un sel de ce composé.
PCT/US2007/084573 2006-11-13 2007-11-13 Procédés pour préserver la fonction rénale au moyen d'inhibiteurs de xanthine oxydoréductase WO2008064015A1 (fr)

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AU2007323919A AU2007323919A1 (en) 2006-11-13 2007-11-13 Methods for preserving renal function using xanthine oxidoreductase inhibitors
KR20157001953A KR20150024919A (ko) 2006-11-13 2007-11-13 크산틴 옥시도리덕타아제 억제제를 사용하여 신장 기능을 보존하는 방법
CN200780049607A CN101677999A (zh) 2006-11-13 2007-11-13 使用黄嘌呤氧化还原酶抑制剂保护肾功能的方法
CA002669935A CA2669935A1 (fr) 2006-11-13 2007-11-13 Procedes pour preserver la fonction renale au moyen d'inhibiteurs de xanthine oxydoreductase
RU2009122505/15A RU2508099C2 (ru) 2006-11-13 2007-11-13 Способы сохранения функции почек с использованием ингибиторов ксантин оксидоредуктазы
KR1020167005469A KR20160031040A (ko) 2006-11-13 2007-11-13 크산틴 옥시도리덕타아제 억제제를 사용하여 신장 기능을 보존하는 방법
EP07864338A EP2101761A4 (fr) 2006-11-13 2007-11-13 Procédés pour préserver la fonction rénale au moyen d'inhibiteurs de xanthine oxydoréductase
JP2009536541A JP2010509372A (ja) 2006-11-13 2007-11-13 キサンチン酸化還元酵素阻害剤を使用する腎機能保持方法
MX2009004984A MX2009004984A (es) 2006-11-13 2007-11-13 Metodos para conservar la funcion renal utilizando inhibidores de oxidoreductasa de xantina.
KR1020097012310A KR20090103879A (ko) 2006-11-13 2007-11-13 크산틴 옥시도리덕타아제 억제제를 사용하여 신장 기능을 보존하는 방법
BRPI0718611-8A2A BRPI0718611A2 (pt) 2006-11-13 2007-11-13 Métodos para preservar a função renal utilizando inibidores da xantina oxidoredutase.

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WO2011141431A1 (fr) 2010-05-10 2011-11-17 Menarini International Operations Luxembourg S.A. Association d'inhibiteurs de la xanthine oxydase et d'antagonistes du récepteur de l'angiotensine ii et son utilisation
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WO2011159745A1 (fr) * 2010-06-16 2011-12-22 Takeda Pharmaceuticals North America, Inc. Nouvelles formes pharmaceutiques à libération modifiée d'inhibiteur de xanthine oxydoréductase ou d'inhibiteurs de xanthine oxydase
WO2011162390A1 (fr) 2010-06-25 2011-12-29 帝人ファーマ株式会社 Agent thérapeutique à libération prolongée contre l'hypertension et l'insuffisance rénale
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JP2016188231A (ja) 2016-11-04
JP2010509372A (ja) 2010-03-25
JP6233899B2 (ja) 2017-11-22
JP2014012726A (ja) 2014-01-23
CA2669935A1 (fr) 2008-05-29
MX2009004984A (es) 2009-09-23
RU2009122505A (ru) 2010-12-20
US20080269226A1 (en) 2008-10-30
EP2101761A4 (fr) 2010-01-27
AU2007323919A1 (en) 2008-05-29
BRPI0718611A2 (pt) 2014-02-25
KR20090103879A (ko) 2009-10-01
CN101677999A (zh) 2010-03-24

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